Transcriptional modulation is a promising approach to neuroprotection in Huntington's disease (HD). Our preliminary data indicates that transcriptionally active compounds like histone deacetylase (HDAC) inhibitors and aureolic acid antibiotics including mithramycin are among the most promising potential treatments available for HD. Phenylbutyrate is the HDAC inhibitor most developed for human use and with the best evidence for brain bioavailability. Mithramycin is used to treat Paget's disease, several types of malignancy, and hypercalcemia of malignancy and has the greatest efficacy in HD transgenic mice to date. The safety, tolerability, and efficacy of these agents is completely unknown in HD or other neuro-degenerative disorders. This project will test the feasibility of these medications in HD in large scale trials of efficacy. In aim one, we will examine whether phenylbutyrate is safe and tolerable for use in HD patients and whether it can improve any symptoms or biological markers of HD. A randomized double-blind placebo-controlled long-term safety and tolerability trial of phenylbutyrate in HD patients will be performed. We will assess the impact of phenylbutyrate treatment on: standardized clinical ratings of motor function, cognition, behavior, and functional capacity. We will also examine In vivo markers of neurodegeneration and transcriptional modulation including proton magnetic resonance spectroscopy for lactate and NAA, and peripheral markers of transcriptional modulation, histone acetylation, and phenylbutyrate activity. In aim two, we will examine whether mithramycin is safe and tolerable in long-term use in HD patients and whether it can improve any symptoms or biological markers of HD. Following an open label dose-ranging trial in which a maximally tolerated dose will be determined, subjects will be randomized into a double-blind placebo controlled safety and tolerability trial of mithramycin using intermittent infusion. We will also assess the impact of mithramycin treatment on; standardized clinical ratings of motor function, cognition, behavior, and functional capacity. We will examine In vivo markers of neurodegeneration including proton magnetic resonance spectroscopy of the basal ganglia and cortex, and peripheral markers of mithramycin activity.